The value of nutritional supplements of elemental zinc is well established. Although zinc has been known to be essential for plant growth for more than a century, its essentially for the normal growth of animals was reported in 1934 and for man in 1963. Hypogonadism in males, skin changes, poor appetite, and mental lethargy are but some of the observable effects related to zinc deficiency in man. Carbonic anhydrase was the first metalloenzyme discovered in the 1930's. Today, approximately 100 enzymes, many of them essential to human well-being, have been found to contain zinc, and the evidence is strong that zinc is required for many (if not all) of these enzymes to express their activity. Several enzymes required for nucleic acid metabolism have been shown to require zinc. In this group are ribonucleic acid (RNA) and deoxyribonucleic acid (DNA) polymerases, deoxythymidine kinase, and reverse transcriptase. It has been shown experimentally that the activity of deoxythymidine kinase in rapidly regenerating connective tissue decreases as early as six days after animals are placed on a zinc-deficient diet. This metabolic defect resulting from nutritional zinc deficiency is an indication of the fundamental importance of zinc for cell division and protein synthesis.
Until recently, zinc deficiency in man was considered unlikely because of the widespread availability of zinc in nature. However, recent evidence suggests that nutritional zinc deficiency may be common among the people of many developing countries where they subsist on high cereal protein diets. Only recently has it been recognized that the phytate content of such diets severely restricts zinc availability, which translates nutritionally to markedly depressed zinc absorption in man under many practical circumstances. Marginal zinc deficiency may be widespread even in the United States because of self-imposed dietary restrictions, use of alcohol and cereal proteins, and the increasing use of refined foods which decrease the intake of trace elements. As meat is a major dietary source of zinc, vegetarians who consume cereals as a major source of protein may be in double jeopardy of zinc deficiency.
Therapeutically, zinc has a vital role in certain diseased or debilitated states. Zinc therapy is life saving in acrodermatitis enteropathica, a genetic disease caused by an autosomal recessive trait, which, although rare, had an extremely high mortality rate until it was discovered in 1973 that chronic administration of oral zinc salts was not only life saving but capable of lifetime control of the disease. Zinc supplementation markedly improves wound healing in zinc-deficient individuals. Zinc deficiency is an important feature in many cases of sickle cell anemia characterized by growth retardation and hypogonadism, and zinc appears to have a pharmacological anti-sickling effect. Zinc has also been shown to be beneficial in the relief of acute inflammatory conditions associated with rheumatoid arthritis.
The safety of zinc supplements in excess of the amounts found in a normal diet is well documented. Although excessive zinc produces toxic symptoms, such symptoms are rare. An acute dose of 2 g of zinc sulfate has been recommended as an emetic. Except for extremely large doses, zinc is non-toxic. Nevertheless, it has been established that the chronic ingestion of zinc in daily amounts in excess of about 100 mg, i.e. about seven times the recommended daily allowance (RDA) of zinc as a nutritional supplement, can in some individuals, result in the depression of blood levels of the beneficial form of circulating lipoprotein known as high-density lipoprotein (HDL). It is further known that the biochemical mechanism that is responsible for this effect is the competitive inhibition of the absorption of cupric ion, Cu.sup.2+, from the gut by the presence therein of greater-than-normal amounts of zinc ion, Zn.sup.2+. Both ions rely upon the intermediacy of the metallothionine protein for transport across the gut wall into the bloodstream. Although cupric ions interact more strongly with metallothionine than do zinc ions, the presence of a relatively large amount of zinc ions can suppress the absorption of cupric ions by direct competition for the available metallothionine. The ultimate effect of this competitive inhibition of the absorption of copper is the undesirable depression of circulating HDL because the cupric ion is an essential component of one of the enzymes in the series that synthesizes HDL in the body. It is further known that the inhibition of Cu.sup.2 + absorption from the gut by Zn.sup.2+ can be overcome if the individual who is ingesting the relatively large amounts of Zn.sup.2+ co-ingests about one to two RDAs of Cu.sup.2+. The RDA for copper is 2 milligrams. A modest increase in copper intake is effective because of the aforementioned greater affinity of cupric ion for metallothionine, relative to the affinity of zinc ion for metallothionine.
Until the present time, the more or less water-soluble zinc compounds such as the sulfate, chloride, acetate, gluconate, and the like, have been formulated as solid tablets or enclosed in gelatin capsules which are swallowed whole. Accordingly, the taste buds and other taste apparatus in the mouth and throat are not affected. These formulations generally dissolve in the gastric juice of the stomach and release zinc ions to be absorbed into the system via the stomach and intestines. It was found by a serendipitous observation of G. A. Eby, D. R. Davis, and W. W. Halcomb as reported in "Reduction in Duration of Common Colds by Zinc Gluconate Lozenges in a Double-Blind Study," Antimicrobial Agents and Chemotherapy, 25(1), pp. 20-24 (1984) that when modest quantities of zinc are slowly ingested by mouth so that the interior surfaces of the mouth and throat are intermittently bathed in a solution of ionic zinc, both the time course and the severity of the symptoms of the common cold are remarkably altered in a favorable way. Their double blind clinical study in 65 humans showed that allowing a tablet containing about 23 mg of elemental zinc, such as zinc gluconate, to slowly dissolve in the mouth once every two hours during 12 to 16 hours a day (the waking hours) reduced the duration of colds from 10.8 days in the untreated group to 3.9 days in the zinc-treated group; and at every time after about one day, the zinc-treated patients had a great reduction in cold symptoms compared to the patients who did not receive zinc. While the reported observations are highly significant both from the point of view of statistical validity and of the importance of these observations to public health, the authors stated repeatedly in their paper that the disagreeable taste of the zinc gluconate tablets was a serious problem. Many patients receiving zinc gluconate discontinued the treatment on the first day "due to objection to the treatment." The authors stated that "the zinc gluconate lozenges tablets! we used caused an unexpected unpalatability and distortion of taste in many subjects . . . " and mentioned "the somewhat bitter aftertaste which some people report for zinc gluconate." Furthermore, "unpalatable taste," "distortion of taste," and "mouth irritation" were common objections.
The original observation of the efficacy of unflavored zinc gluconate tablets has received strong confirmation. Two large, double-blind, placebo-controlled clinical studies have been carried out and reported in the medical literature. The first was carried out at the Dartmouth College Cold Clinic in New Hampshire and reported by J. C. Godfrey, B. Conant Sloane, D. S. Smith, J. H. Turco, N. Mercer, and N. J. Godfrey in "Zinc gluconate and the common cold: A controlled clinical study," Journal of International Medical Research, 20(2), pp. 234-246 (1992). This study used sugar-based lozenges containing zinc gluconate equivalent to 23 mg of zinc, and glycine, prepared by serial dilution technology to produce a formulation according to U.S. Pat. No. 4,684,528 and U.S. Pat. No. 4,758,439. Participants in this study who met protocol requirements and who received active lozenges within two calendar days of the onset of cold symptoms and dissolved them in their mouths every 2 hours while awake, as specified in the protocol carried out under a U.S. Investigational New Drug Application, experienced colds that lasted only 58% (mean duration) as long as patients who received a placebo. Patients in this study who received the active medication also experienced significant reductions of symptom severity and duration as compared to those who received the placebo.
The second double-blind study was done at the Cleveland Clinic Foundation by S. B. Moussad, M. L. Macknin, S. V. Medendork, and P. Mason and reported in "Zinc gluconate lozenges for treating the common cold," Annals of Internal Medicine, 125(2), pp. 81-88 (1996). Patients who qualified for this study had cold symptoms for no more than 24 hours prior to entry. The study used zinc gluconate lozenges containing glycine, prepared in the same manner as for the Dartmouth study but containing just 13.3 mg of zinc. When the data from this study were analyzed on the same statistical basis as the Dartmouth study, i.e., using only the 83 out of 100 patients who met all criteria specified in the protocol, it was found that patients who took active medication had colds for only 52% as long as those who got a placebo. As in the Dartmouth study, patients in this study also experienced a rapid reduction in symptom severity, compared to those on a placebo.
As noted, zinc gluconate by itself has a very bad taste which may be overcome by formulations containing an excess of glycine or certain other selected amino acids such as described in U.S. Pat. Nos. 4,684,528 and 4,758,439. It has been found that nutritionally useful copper salts such as cupric gluconate, cupric sulfate, cupric acetate, and cupric chloride also have undesirable organoleptic properties by themselves or in admixture with zinc gluconate in proportions (e.g., 1/33 mole of cupric salt per mole of zinc salt) that are useful to prevent the aforementioned adverse effect on HDLs. Accordingly, in order to take advantage of the important effect of zinc upon the common cold while negating any potential adverse effect of zinc ingestion upon the high density lipoproteins of human beings it is necessary to develop a formulation or formulations of pharmaceutically acceptable zinc salts combined with a minor proportion of cupric salts which are palatable enough to be taken with the frequency necessary to suppress symptoms of the common cold.
Another reason for developing zinc formulations having acceptable taste is to permit an increased or prolonged oral dosage. As described above, it has been found that the ingestion of zinc as tablets or capsules which pass directly to the stomach before disintegrating is ineffective for providing a zinc supplement for certain applications, including the control of cold symptoms. When zinc-containing lozenges are dissolved orally for treating an average common cold, no affect has been shown to occur on HDLs. However, if a user decides to take the zinc-containing lozenges on a daily basis as a dietary supplement or to control respiratory allergies, or has numerous colds occurring close in time, such prolonged intake of zinc can affect HDLs.